Peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) 是當細胞受到外在環境刺激 (如：冷) 會被大量誘導表現，且其表現的形式與調控細胞能量代謝與適應性產熱有關。在本實驗室的研究中發現Bhlhe40，這個可被retinoic acid所誘導的basic helix-loop-helix蛋白質，可以抑制MyoD活化PGC-1α promoter的能力。而細胞內調控Bhlhe40的表現量會因不同類型的細胞面對不同生理的變化過程而有所差異，包括生理節律時鐘、缺氧、細胞分化等。此外，本實驗室目前發現PGC-1α與Bhlhe40無論是在in vitro或是in vivo中都具有很強的結合能力，我們同時也發現在PPARγ活化UCP-1 promoter的調控上，Bhlhe40對於PGC-1α協同活化PPARγ具有拮抗的功能，而此拮抗的效果會因PGC-1α的表現量足夠而被恢復。除此之外，Bhlhe40需要與HDAC-corepressor 進行交互作用的domain才具有此拮抗的功能。而PGC-1α與Bhlhe40這兩個轉錄因子主要利用兩者的N端進行交互作用。我們也發現PGC-1α與Bhlhe40這兩個因子表現的形式，在運動後的老鼠肌肉中或是當細胞處於缺氧狀態下會有所不同，證明在肌肉細胞能量代謝中，由Bhlhe40抑制 PGC-1α協同活化功能具有重要的生理意義。The expression pattern and induction by cold-exposure have implicated peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) in the regulation of metabolism and adaptive thermogenesis. Our recent studies have found that Bhlhe40, a retinoic acid-inducible gene encoding a basic helix-loop-helix (bHLH) protein, can repress MyoD activated PGC-1α promoter. The expression of Bhlhe40 is regulated in a cell type-specific manner in various biological processes, including circadian rhythms, hypoxia, and cellular differentiation. Furthermore, our preliminary works found that PGC-1α and Bhlhe40 had strong binding affinity both in vitro and in vivo. We also found that Bhlhe40 antagonizes the coactivational effect of PGC-1α on PPARγ activated UCP-1 promoter and this antagonism can be relieved when saturation amount of PGC-1α is present. And this antagonistic effects require the HDAC-corepressor interaction domain of Bhlhe40. The interacting domains in PGC-1α and Bhlhe40 have been localized to the N-terminus of these two factors. Distinct expression patterns of these two factors were observed in muscles of exercised mice and in cells kept in hypoxia, demonstrating the physiological importance of Bhlhe40-mediated repression of PGC-1α in muscle metabolism.
